diagnosis and Treatment of Leprosy
Content
CLINICAL
REVIEW
An update on the diagnosis and treatment of leprosy
Samuel L. Moschella, MD Burlington, Massachussetts
A
lthough the World Health Organization (WHO) has assumed the authoritative role for the guidelines for the diagnosis and treatment of leprosy, certain endemic countries such as India and Brazil and countries with traditional interest in the disease such as England and the United States have utilized their own programs which have been modified by the WHO. The prevalence of leprosy in endemic areas has been significantly reduced, but unfortunately the incidence continues to be the same. However, the WHO is optimistic about the elimination of leprosy as a public health problem in the near future; such optimism is not shared by many leprologists. The practicing physician especially in the non-endemic areas, such as the USA, should be aware of the current diagnostic and therapeutic approach to leprosy as recommended not only by the National Leprosy Center of the USA and its satellite clinics, but also by the WHO. If the practicing dermatologist wants to treat leprosy and become a ‘‘dermatoleprologist,’’ it is mandatory that he is knowledgeable about its diagnosis, treatment, reactions, the associated neuritis, and the prevention and management of its disabilities. With the potential decline of leprosy, leprosy control will become part of primary health care, which must promote early detection, adequate treatment, prevention, and management of disabilities.
GLOBAL SITUATION1,2
Over the years through expert committees and study groups, the WHO has assumed responsibility for recommending guidelines especially to underdeveloped countries for the management of leprosy. These guidelines take into consideration not only
From the Department of Dermatology, Lahey Clinic Medical Center. Funding sources: None. Conflicts of interest: None identified. Reprint requests: Samuel L. Moschella, MD, Dermatology Department, Lahey Clinic Medical Center, 41 Mall Road Burlington, MA 01805. E-mail: [email protected]. J Am Acad Dermatol 2004;51:417-26. 0190-9622/$30.00 ª 2004 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2003.11.072
their efficacy, but also the cost and availability of the necessary personnel. Although it has become literally the authoritative resource, one must recognize that in some endemic areas such as Ethiopia, Brazil, and India, and in the non-endemic areas such as the United States and England, there are research and study centers assessing, developing, and recommending modifications of the current diagnostic and therapeutic approaches. Leprosy is regarded as a special public health problem because of its capacity to cause permanent disabilities with their social consequences of discrimination and stigma. The three main objectives in controlling leprosy are to interrupt transmission, cure patients, and prevent development of deformities. In 1981, the number of leprosy patients in the world was more than 12 million. With the implementation of multiple drug therapy (MDT) in 1982 and the World Health Assembly resolution in 1991, the global effort for the ‘‘Elimination of Leprosy as a Public Health Problem’’ was prioritized and has resulted in over 10 million patients being cured. In countries with more than 100 cases registered, the WHO reported in January 2002 that, in the year 2000, a total of 597,232 cases were registered and 719,330 new cases were diagnosed.1 This report emphasized the reduction of the global prevalence from 12 per 10,000 in 1985 to slightly below 1 per 10,000 in 2002. Of the 122 countries in which leprosy was considered endemic, 107 have achieved the ‘‘elimination target’’ (1 per 10,000). Approximately 83% of the leprosy cases live in six countries: Nepal, Madagascar, Myanmar, Indonesia, and especially India and Brazil. As of 2001, there are 6,518 ‘‘active’’ cases of leprosy registered in the USA.3 The number of new cases remained about the same until the last 10 years during which there has been a significant increase. This increase may be a result of increased case detection campaigns and expansion of geographical coverage by leprosy services in endemic countries. Encouraged by the success of the multiple drug therapy, the WHO assembly adopted, in 1991, a declaration to eliminate leprosy as a public health problem by the year 2000. Since it was apparent that the goal was not to be achieved, a global alliance for 417
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the elimination consisting of a core group of the governments of leprosy endemic countries, the Nippon Foundation, the International Federation of Antileprosy Association, Novartis, and the WHO was formed. It will cooperate with other institutions to eliminate leprosy by the end of 2005. The past pessimism by various authors, which I share, still persists.4 This lack of enthusiasm is fueled by the following: 1. There is no sound evidence that the leprosy elimination strategy has had an impact on transmission so far. 2. The incidence has increased in spite of the significant reduction of the prevalence. 3. Leprosy is not only a bacterial, but also an immunologic disease. Failure of early diagnosis and treatment will increase neural disease. After patients are cured by MDT, a quarter of them experience immunologic nerve damage reactions. Emphasis on elimination can eclipse the quality of care necessary to prevent the disability, which will prevail long after 2005. 4. Other areas that need to be addressed which could have a significant impact on elimination are the recognition of the hidden prevalence, the subclinical infected, the possible role of the non-human reservoir or of sources of infection in the environment responsible for transmission, the need for a skin or serologic tests to diagnose subclinical, early, or questionable cases, the availability of an effective, cheap, proven prophylactic and possible immunotherapeutic vaccine, and the need of personnel capable of making an early diagnosis and to clinically differentiate paucibacillary (PB) and multibacillary (MB) disease.
At the Seventh Meeting of the WHO Expert Committee on Leprosy in 1997, a case of leprosy was defined as an individual who has not completed a course of treatment and has one or more of the three cardinal signs:7 Hypopigmented or reddish skin lesions with loss of sensation Involvement of the peripheral nerves as demonstrated by their thickening and associated loss of sensation Skin-smear positive for acid-fast bacilli The specificity of the diagnosis based on the presence of anesthetic hypopigmented or erythematous macular lesions is reduced in multibacillary cases because the lesions can be less distinct and less anesthetic. Consequently macular anesthetic lesions as a single diagnostic criterion for multibacillary (MB) disease has resulted in up to 30% of patients to be missed; this contrasts with patients with distinct maculoanesthetic lesions of paucibacillary (PB) disease, which are reportedly diagnostic in 90% of cases. In Ethiopia where all 3 cardinal signs were used, the diagnostic sensitivity was 97%.1 Peripheral nerve enlargement usually appears later than skin lesions. The most commonly involved nerves are the ulnar and common peroneal. The presence of one or more enlarged nerves is seen more commonly in multibacillary disease. False positive reporting of nerve involvement may result from poor examination technique or the nonspecific enlargement of nerves such as in manual workers. To improve the certainty of the diagnosis of leprosy, a balanced approach to the diagnosis is strongly recommended and would be the appreciation of the presence of a thickened nerve and one other diagnostic sign such as: typical hypopigmented or erythematous skin lesions with or without sensory loss or typical nerve-function impairment such as loss of sensation of palms or soles Leprosy can present as a purely neural disease without skin lesions; the so-called neuritic leprosy. Nerve biopsy is confirmatory. The incidence is 0.5% in Ethiopia, 4.6% in India and 8.7% in Nepal. The diagnostic specificity of skin smears is almost 100%; however, its sensitivity is rarely more than 50% because smear positive patients represent only 1050% of cases. The inherent problems of skin smears are the logistics and the reliability of the technique of taking, staining, and interpretting the slide. Skin smears identify those with multibacillary disease who are the most infectious and also those patients who are experiencing clinical relapses.
DIAGNOSIS OF LEPROSY5,6
Leprosy is a slowly progressive infectious disease caused by Mycobacterial leprae and complicated by potential intermittent hypersensitivity reactions (the so-called lepra reactions). It is highly infective with low pathogenicity and virulence and has a long incubation period. The skin, superficial peripheral nerves, anterior chamber of the eyes, and testes, all cooler parts of the body are the most frequently affected organs. Its geographic distribution varied in the past, but presently it is endemic mainly in subtropical areas. Early accurate diagnosis and therapy are most important for the control of the disease, the management of the patient, and prevention of disabilities. Underdiagnosis promotes transmission and results in unnecessary suffering and deformities; overdiagnosis is responsible for unnecessary treatment, stress, stigma, and misleading epidemiologic statistics.
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Tissue biopsies are used to make a histologic diagnosis, to classify the disease, to provide material for inoculation of footpad of mice, and for research purposes. The biopsy cannot be regarded as the diagnostic gold standard since a number of them can be nondiagnostic or doubtful. In practice, a clinical and histopathologic correlation may be necessary for diagnosis. Although the histopathologic diagnostic specificity of non-reactive disease is high, the histopathologic differentiation of relapse from reversal can be difficult or impossible. In a study in China, immunohistopathologic studies staining biopsies of PB patients with phenolic glycolipid-1 antigen proved to be more specific diagnostically than routine hematoxylin and eosin histopathologic examination.8 In the field, the diagnosis and classification of leprosy have been based on clinical examination and skin smears when facilities are available. Diagnostic tests such as histologic examination of involved tissues, inoculation of footpads of mice, serologic and skin testing, and polymerase chain reaction studies have been confined to countries which have such studies available to their practicing physicians and in academic and research centers. Two laboratory tests, which so far have not played a significant role in the diagnosis of leprosy, are the serological tests for anti-PGL-1 antibodies and the PCR test. There are two methods to determine the presence of anti-PGL-1 antibodies, the M. leprae particle agglutination assay (MLPA) and the enzymelinked immunosorbent assay which was further refined into a ‘‘dipstick’’ assay which has greater specificity.9 The PGL-1 antibody testing is specific and sensitive in patients with MB disease, but unfortunately it is not very helpful in the diagnosis of PB disease and is unable to predict, among contacts of known cases in the general population, who will develop the disease. PCR testing is a highly sensitive and specific diagnostic tool. Unfortunately, in countries where it is available, such as at the National Hansen Disease Center, Baton Rouge, Louisiana, USA, it has not proved so far to be as effective diagnostically as anticipated in indeterminate or paucibacillary disease.10
CLASSIFICATION OF LEPROSY11
In 1966, Ridley and Jopling created a classification of leprosy, based on the immunologic response of the host to M leprae, into a five-group system: TT (polar tuberculoid), BT (borderline tuberculoid), BB (borderline), BL (borderline lepromatous), and LL (polar lepromatous) (Table III).12 In 1982, the WHO study group for chemotherapy for control programs recommended the classification of all patients be based on Ridley-Joplin classification and the esti-
mated bacterial load in skin-slit smears. The TT and BT patients who had a bacillary index (BI) # 2+ were classified as paucibacillary disease, and BB, BL, and LL patients who had a BI > 2+ were classified as multibacillary disease. The BI reflects the number of acid-fast bacilli per average oil immersion field and is expressed on a 0-to-6+ semilogarithmic scale; BI of 2+ is the presence of 1 to 10 bacilli per 10 oil immersion fields. In 1988, the WHO Expert Committee on Leprosy, to avoid further treatment failure of PB patients with positive skin-slit smears, recommended such cases be classified as multibacillary disease and consequently any patient with a positive skin smear is classified as multibacillary disease. In the USA, the Public Health Service recommends that the classification of leprosy should be made on clinical evaluation, and skin smears from several sites and skin biopsies which can be read if necessary by the National Hansen’s Disease Center, Baton Rouge, Louisiana. The Ridley-Jopling classification is used. In general, PB disease is equivalent to indeterminate I, TT (tuberculoid), and BT (borderline tuberculoid) disease, and MB is equivalent to BB (borderline), BL (borderline lepromatous) and LL (lepromatous) disease with the Ridley-Jopling classification. In the US, the terms paucibacillary and multibacillary are used to direct drug therapy. In 1998, the WHO Expert Committee on Leprosy declared skin-slit smears were not essential for multiple drug therapy (MDT) and the number of clinical lesions present was to be the basis for classification.13 This was motivated by the unavailability or unreliability of the skin smear in many programs and the potential for transmitting HIV disease and hepatitis by unsterile techniques. The recommended clinical diagnostic guidelines are as follows: patients who are not experiencing reactions and have less than five skin lesions are to be classified as paucibacillary disease (PB), and those with greater than five skin lesions are to be classified as multibacillary (MB). Unfortunately, there will be a sufficient number of MB cases classified as above PB to cause some concern because of the potential for their inadequate treatment.
REACTIONS13,15
There are two main categories of reactions in leprosy: Type I14 reaction, which is called a reversal lepra reaction and is an example of Type IV cell mediated allergic hypersensitivity reaction (Coombs and Gell); and Type II lepra reaction,15 which is reported as erythema nodosum leprosum and is an example of Type III humoral hypersensitivity reaction (Coombs and Gell) (Table II). Among the
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precipitating factors are physical and mental stress, multiple drug therapy, vaccines, pregnancy, surgical procedures, injuries, intercurrent infections, and other antibacterial treatments. Inflammatory edema of hands, feet, and face is seen in both types and is a sign of severe reaction. Nerve tenderness and pain are often associated with both types. The most common and frequent nerves involved are the ulnar, the facial, median, common peroneal, and posterior tibial nerves. The related physical impairment may be acute and dramatic such as facial paralysis or foot drop. The reversal reaction (Type I)14 occurs in borderline tuberculoid (BT), borderline (BB), and especially borderline lepromatous (BT) and possibly in tuberculoid (TT) leprosy. The present skin lesions become more erythematous, edematous, raised, and rarely ulcerated. Patients with BL, BB, and occasionally BT disease exhibit not only changes in the existing skin lesions but may develop similar new lesions. Erythema nodosum leprosum (ENL) (Type II) reaction15 is immunologically characterized by immune complex deposition in tissue space, blood, and lymphatic vessels, which give rise to acute inflammatory foci. It usually occurs most frequently in patients with LL and occasionally in those with BL. Increased cell-mediated immunity may play a role in the precipitation of an attack. The tumor necrosis factor alpha is elevated in ENL. During therapy or occasionally during pregnancy, patients with BB to LL disease can develop ENL characterized by the sudden appearance of crops of erythematous tender nodules or plaques, and rarely vesicular, pustular, or necrotic lesions. The eruption favors the extensor surfaces of the extremities and face. Other signs and symptoms are fever and malaise, iritis, epistaxis, muscle and bone pain, nerve pain, joint pain, lymphadenitis, epididymo-orchitis, and proteinuria. A third rare type of reaction, the Lucio phenomenon,15,16 is usually restricted to Central and South America and immigrants from those areas. It occurs in a subtype of lepromatous leprosy called the primary diffuse lepromatous leprosy (la lepra bonita) characterized by a diffuse infiltration of the skin by a granulomatous process heavily loaded with mycobacterium leprae. Significant nasal mucosa involvement usually occurs with subsequent nasal destruction. Ocular and peripheral nerve involvement are significantly less frequent than in the other subtypes of lepromatous leprosy. Intermittent fever, generalized lymphadenopathy, and splenomegaly may be seen. The eruption (the Lucio phenomenon) is characterized by the presence of symmetrical erythematous, black, stellate, necrotic lesions of the
extremities and occasionally the face. The patients are usually on no treatment when it occurs.
HANSEN’S DISEASE AND PREGNANCY20,21
It is not uncommon for leprosy to present itself during pregnancy or early puerperium. Because of alterations in immune responses during pregnancy, leprosy patients who become pregnant are more prone to develop type I and II reactions, a downgrading of their disease, and relapses. Type II reaction usually occurs during pregnancy, especially during the third trimester and lactation. Type I reaction occurs, especially during puerperium. Infants run a relatively high risk of contracting leprosy from untreated mothers, especially if she has BB or LL disease. It has been recommended that rifampin be given only as a single monthly dose during pregnancy, but dapsone and clofazimine can be used or continued. For reactions, prednisone and clofazimine can be given, but thalidomide should be avoided. It is advisable to postpone pregnancy temporarily during post-therapy period if there is evidence of reaction, relapse, or neuritis.
HANSEN’S DISEASE AND HIV DISEASE22,23
Unlike in tuberculosis, HIV disease has not had a significant impact on the clinical course of treated and untreated leprosy. However, it has been reported that the neuritis in co-infected people can be more severe and the reversal reaction may be more frequent after therapy. In endemic areas of HIV disease and leprosy, there does not appear to be a greater incidence of leprosy among HIV patients. It may be because of the very slow proliferation of the bacilli or the prolonged incubation period, or perhaps a particular cellular mechanism involved in its pathogenesis.
THERAPY OF NONREACTIVE DISEASE24-26
In 1981, the WHO Study Group recommended multiple drug therapy (MDT) for the following reasons:24 1. To address dapsone resistance and to discourage resistance to other drugs to be used. 2. To promote compliance and to get away from long-term monotherapy such as dapsone. 3. To keep rifampin in all therapeutic regimens because of its powerful bactericidal action and its effectiveness even when taken once a month. 4. To promote compliance and cost effectiveness. In 1997, the WHO Expert Committee suggested that it might be possible to reduce duration of MDT for multibacillary disease from 2 years to one year and also recommended the treatment of a single PB
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lesion with one dose of ROM (rifampin, ofloxacin, and minocycline).26 The current WHO recommended MDT for adults is as follows: 1. For paucibacillary disease (PB), 600 mg rifampin monthly and 100 mg dapsone daily with six cycles in 9 months. 2. For multibacillary disease (MB), 600 mg rifampin and 300 mg clofazimine monthly and 100 mg dapsone and 50 mg clofazimine daily with 24 cycles in 36 months or 12 cycles in 18 months 3. For single PB lesion, rifampin 600 mg, ofloxacin 400 mg, minocycline 100 mg. Because of a lack of long-term follow-up, this recommendation should be considered experimental. Single-lesion leprosy, which is often indeterminate leprosy, heals spontaneously in 80% of patients. It is too early to determine if those of the 20% who develop classifiable leprosy will benefit from single ROM treatment. It may cure some patients but will only delay the onset of multibacillary disease in others. In the United States, a biopsy of a suspicious lesion is recommended to establish the diagnosis and deliver the appropriate treatment. Other drugs with anti-mycobacterial properties, which may be used if needed as substitutes in the above current therapeutic programs are rifabutin, ofloxacin, sparfloxacin, levofloxacin, minocycline, and clarithromycin. Although the diagnostic and therapeutic guidelines advocated by the WHO have significantly impacted on global prevalence rate, practitioners especially in the USA should be aware that the Public Health service recommends the classifications of the disease into paucibacillary and multibacillary disease for its recommendations for treatment. In the United States, MDT has been standard therapy since the 1970s. During this period, 3 years of daily dapsone, rifampin, and clofazimine was recommended, and if there was suspicion of dapsone resistance, severe and widespread neuropathy, or ocular disease, dapsone was recommended to be given indefinitely. In 1990, a relatively short-term therapy was introduced in the United States under the FDA-approved protocols which has proven very effective and without significant toxicity. The current recommended standard treatment regimens for Hansen’s disease in the United States are outlined in Table I. The strengths of MDT are that it obviates and prevents dapsone resistance, quickly reduces infectivity, and results in fewer relapses and reactions, and consequently, fewer disabilities. The shortcomings of MDT are the long duration of therapy with
Table I. Public health service recommendation for treatment of leprosy
1. Paucibacillary (PB): Dapsone 100 mg daily plus Rifampin 600 mg daily for 1 year 2. Multibacillary (MB): Dapsone 100 mg daily plus Rifampin 600 mg daily plus clofazimine 50 mg daily for 2 years 3. The follow-up: For treated PB disease every 6 months for 5 years and for MB disease every 6 months for 10 years
consequential reduction of compliance, encouragement of default, and creation of operational difficulties. Since WHO/MDT appears to have been effective, safe, and well tolerated and the risk of relapse is low, unlike the USA, the WHO does not advocate posttherapy surveillance. Patients are advised to report as soon as they note any skin, eye, or nerve changes. Fortunately, post-therapy relapse, reaction, and silent neuropathy occur infrequently. Until sufficient data of post-therapy complications exists, treated paucibacillary disease should be followed for at least three to five years, and treated multibacillary disease should be followed for at least five to ten years. Silent neuropathy is described as a progressive sensory or motor impairment which occurs in the absence of cutaneous type I or II reactions and is characterized by a lack of involved nerve tenderness and burning or shooting pain, paresthesias, or numbness.27
VACCINATION
Anti-leprosy vaccination can be immunoprophylactic or immunotherapeutic.28-30 The immunoprophylactic aim is to restore the host recognition of shared mycobacterial antigens to promote TH1 responses to them, to induce CD8 cytotoxic cells, and to downregulate the proportion of T cells producing interleukins 4 and 5. The aim of immunotherapy is to switch off the mechanisms leading to immunopathology and to increase intracellular mechanisms by which bacilli are killed. The first vaccine used was BCG, but its failure to protect certain populations clearly indicated that an improved vaccine against leprosy was needed. Among the vaccines being used or explored are Mycobacterium W. (Talwar, 1978), Mycobacterium ICRC (M avium intracellulare) (Deo et al, 1981), bacillus Calmette´ rin plus heat-killed M leprae (Convit, 1992), Gue Mycobacterium tufu (Iushm and Kalianina, 1995), and Mycobacterium habana (Singh et al, 1997).29 The enthusiasm for use of vaccines has lessened because of the significantly favorable impact of MDT on leprosy. However, one cannot deny the potential usefulness of a proven effective vaccine in highly endemic countries such as India and Brazil. Some of
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Table II. Characteristic features of reactional leprosy
Type I reaction (Reversal) Type II reaction (erythema nodosum leprosum-ENL) Lucio phenomenon
Complication of types of - Rare in Tuberculoid leprosy - Borderline (BB, BT, BL) Clinical features -
-
-
-
-Lepromatous leprosy (LL) and occasionally Borderline lepromatous (BL) Occurs during 6 to 18 - Can occur before months of treatment treatment but tends to occur later in treatment Constitutional signs and - In severe cases constitutional signs symptoms in severe and symptoms cases - Erythematous tender nodules Lesions become appear in crops especially erythematous and extremities and face edematous; in severe cases ulcerate (Lazarine - Vesicular, pustular, suppurative lesions can occur leprosy) - Edema of face, hands, and feet Edema of affected extremities and face may - Orchitis, lymphadenitis, dactylitis, epistaxis, and proteinuria occur
- Diffuse lepromatous leprosy; endemic Mexico and Costa Rica - No constitutional signs or symptoms
Neuropathic and ocular changes
Course
Treatment
- Few days but can be prolonged, frequent, and recurrent - Prednisone, non-steroidal - NSAID, thalidomide, anti-inflammatory drugs increase dose (NSAID) of clofazimine, systemic corticosteroids
- Pain and swelling of one or more nerves; nerve abscesses can form - Sudden appearance of claw hand, foot drop, facial palsy with or without Lagophthalmus and complicating exposure keratitis - Usually persists for few months
- Widespread painful swelling of peripheral nerves - Iridocyclitis and scleritis of eyes
- Pseudomyxedematous facies - Madarosis with or without generalized and diffuse hair loss - Extensive areas of anhidrosis - Early and severe destructive rhinitis - Erythema necrotisans-flame or geographic shaped necrotic lesions anteceded sometimes by hemorrhagic blisters; appear in crops, favor extremities and sometimes the face; heal with superficial scarring - No orchitis - Labs—anemia, elevated sedimentation rate, positive STS - Acral distal symmetrical anesthesia usually with no significant aggravation - Muscle atrophy and paralysis late - Minimal ocular involvement with no iritis - Depends on the severity of the reaction and response to MDT - Systemic corticosteroids - Thalidomide is ineffective
the best information about vaccination is from India where the Mycobacterium W and ICR vaccines are currently being used. In the field, with the use of vaccine ‘‘W’’ as an adjunct to chemotherapy, the following observations were noted:28 1. The vaccine expedited bacterial clearance and accelerated clinical regression of the lesions. 2. It shortened significantly the period of release of the patients from treatment.
3. It was effective in inducing a fall in the bacterial index in multibacillary patients who are poor or nonresponders to the standard multidrug therapy. 4. It promoted the conversion of the lepromin from negativity to positivity. 5. There was a histopathologic upgrading. 6. The vaccine was tolerated and the incidence and severity of the type II reaction was reduced. 7. No increased incidence of neuritis was seen.
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Table III. Ridley-Jopling classification
Characteristics Indeterminate Tuberculoid (TT-Polar) Borderline tuberculoid (BT) Borderline (BB) Borderline lepromatous (BL) Lepromatous (LL + Polar)
Cutaneous
One or few One or few lesions; lesions; hypopigmented sharply or erythematous marginated; scaling macules; favors macules or extremities, buttock, or face plaques; sometimes elevated edges
Neuropathic Lesions slightly changes hypesthetic, no peripheral nerve enlargement
Lesions anesthetic sometimes enlarged nerve in area of lesion
Nil Nil Bacterial (paucibacillary) (paucibacilindex lary) (Ridley’s logarithmic indices) Lepromin Variable Strongly test positive Reactions Nil Rare
Multiple and symmetrical erythematous and copper colored macules, later induration followed by nodulation of face especially ears and nose, extremities especially joints, and trunk; madarosis of eyebrows; nasal mucosal ulceration Usually no Lesions Moderate Lesions sensory slightly anesthetic anesthetic impairment in anesthetic lesions asymmetrical early stages; widespread widespread several later and less and peripheral symmetrical asymmetrical asymmetrical nerves peripheral peripheral peripheral involved neuropathy nerve nerve of arms and involvement involvement legs with stocking and glove anesthesia and of the facial nerve; Eye involvement (conjunctiva, cornea, and iris) 2+-3+ 4+-5+ 6+ and greater Nil or scarce (multibacillary) (multibacillary) (multibacill(paucibacillary) ary) or multibacillary Several succulent Many, Few to many roughly plaques erythematosymmetrical with sharply hypochromic shiny demarcated plaques with erythematous central area scaling and and edges surface and sometimes sloping into well-defined hyposurrounding margins pigmented normal skin; which macules, large may have papules, erythematous small satellite nodules irregular lesions and with infiltrated is usually sloping bands with annular edges central uninvolved anesthetic areas Weakly positive Reversal (Type I) Negative Reversal (Type I) Negative Reversal (Type I) and/or ENL (Type II) Negative ENL (Type II)
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TREATMENT REACTIONS
Unfortunately in spite of the significant advances in the chemotherapy of the disease in the last ten years, the understanding of the etiology and management of reactions has not changed much. MDT has not significantly impacted on the incidence of the reversal reaction (Type I). The treatment of the reaction14,16,31 depends on its severity, the type of the reaction, the presence of neuritis, facial involvement in Type I reaction, pregnancy, and drug allergies or adverse drug reactions. If Type I reaction14 is severe or associated with neuritis or facial lesions are involved, systemic corticosteroids are indicated. In milder cases without neuritis, the nonsteroid antiinflammatory drugs may be helpful. With the use of clofazimine in the WHO multidrug therapy, the frequency of ENL Type II reaction has been significantly reduced to as low as 5%. In Type II reaction15,16,31 without significant neuritis, thalidomide is effective, but in the presence of neuritis or iritis, systemic corticosteroids are necessary. Topical steroids and atropine are used for reactive iritis. Clofazimine in higher doses can sometimes permit the use of lower doses of corticosteroids. Colchicine32 and pentoxifylline33 have been reported to be effective and may be useful as adjunctive drugs in the treatment of Type II reactions. In refractory cases immunomodulatory agents such as cyclosporin A,34 and intravenous IgG might be considered. Lucio phenomenon17,18,19 is usually controlled by systemic corticosteroids. In the late 1940s and early 1950s, Mexican leprologists reported the control of Lucio phenomenon in untreated patients with the initiation of dapsone therapy;35 unfortunately in my limited experience, monotherapy with dapsone in the past and MDT presently did not make a significant therapeutic impact on the Lucio phenomenon. Thalidomide is ineffective. In severe, non-responding cases, immunomodulatory and cytotoxic drugs, such as Imuran or cyclophosphamide with systemic corticosteroids with or without plasmapheresis have been used.
involved followed by the feet and eyes. There is an estimated 3 million people with physical impairments with resultant disabilities. Approximately 4% of newly diagnosed patients present with grade II disabilities, which are visible deformities or damages. However, grade I disability, that is the presence of anesthesia without damage is important because these patients are at serious risk of developing serious impairments and deformities. The reported incidences of grade II disabilities are 3% in patients in Southeast Asia, 11% of patients in Africa, and 5% of patients in America. Any leprosy program must incorporate the prevention of disabilities and rehabilitation. Among the important efforts for prevention are an initial and periodic measurement of neural impairment, aggressive treatment of reactions, provisions for the therapy and prevention of injuries to the hand, of foot ulcers, of eye disease, and their complications, and instructions in self-care. The best methods for early detection of nerve impairment are palpation for nerve enlargement and use of sensory testing. Early detection and treatment of reactions significantly reduce and prevent nerve damage with its resultant impairment. The initiation of systemic steroid therapy depends on the magnitude and duration of nerve function impairment and/ or nerve tenderness. It has been reported that 7% of new patients have at first examination silent neuropathy; 75% of all silent neuropathy was diagnosed during the first year of treatment.27 Patients with extensive skin involvement, more than three enlarged nerves or a positive skin smear, are at a greater risk to develop silent neuropathy. The leprous neuropathy responds to a prednisone taper over about a four to six month period. Patients treated for early nerve impairment regain 60% of their nerve function. Neural impairment up to six months duration may be benefited by systemic corticosteroid therapy. The role of surgery in the management of nerve involvement is controversial. There is no data to suggest that steroids given prophylactically prevent impairment.
PREVENTION OF DISABILITIES AND REHABILITATION36,37
The socioeconomic impact resulting from the physical and psychological disabilities of leprosy continues to be a burden in endemic countries. 25% of leprosy patients have some degree of disability, which are greatest in patients with BL and LL disease. It is greater in the older age group and males. Duration of disease and disability are directly proportional to each other. Hands are most frequently
CONCLUSIONS
In spite of its relative simplicity, the classification of leprosy into paucibacillary and multibacillary disease based on lesion count in conjunction with an MDT program has proven to be effective in the reduction of the prevalence without significant relapse or Type I and II reactions. In fact, the incidence and severity of these reactions, especially Type II, have been reduced. When facilities are available to do the necessary laboratory studies, it is advisable to
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continue to use the Jopling-Ridley classification for scientific communications, teaching, and patient care. Because the incidence appears to have remained stable in spite of MDT, the projection of the WHO program for the eradication of leprosy by 2005 appears to be unrealistic. In the absence of a proven cost effective vaccine and because of the time constraints for vaccine trials, there is presently no alternative to MDT in trying to break the chain of transmission of M. leprae, however. I share the pessimism of some leprologists. The question being asked is: will the repeated postponements of the goal elimination dates undermine the confidence and support of the involved governments, institutions, and public for this strategy? I would like to echo support for the stance of Vissehedigk et al2 which is: sustainable leprosy control which consists of early detection of patients, adequate treatment, and providing comprehensive care for the prevention of disabilities and rehabilitation, and continuous research to close the substantial gaps in the knowledge of leprosy transmission and epidemiology should be our goal for the foreseeable future rather than elimination. Unlike tuberculosis, HIV disease has not yet demonstrated a significant impact on leprosy and vice versa. Pregnancy can precipitate relapse, as well as Type I and Type II reactions. Unfortunately, there are no skin tests or serologic studies that facilitate the recognition of ‘‘carriers,’’ or the diagnosis of paucibacillary disease. The pathogenesis and treatment of the Lucio’s phenomenon need to be established. In endemic regions, leprosy continues to be a public health problem. Defining leprosy control purely by prevalence side-steps the real issues such as: 1. Control programs need tests such as a skin or serologic test for recognition of ‘‘carriers’’ in order to help reduce the incidence. 2. Research is needed to shorten treatment schedules and to reduce defaulter rates and costs. 3. Treatment of the infection, reactions, and neuritis is still far from ideal. 4. The use of an effective vaccine may play a major role in the prophylaxis and therapy of leprosy in high-risk regions. 5. Research into the true incidence of leprosy in endemic areas is essential. 6. Control programs need a more detailed understanding of M. leprae to permit more logical interventions. 7. It is essential to minimize irreversible physical damage, which leads to disability and stigmatization.
Although, the prevalence rate should continue to decline, the major problems such as the disabilities among the old ‘‘cured’’ patients and those of the newly diagnosed patients must continue to be addressed. Because of the lack of the knowledge necessary to reduce the incidence of leprosy, we have to continue to invest heavily in the effort to reduce the prevalence and hopefully the incidence secondarily. It is also important to plan for the future by making leprosy control part of primary health care, which should promote early detection and adequate treatment as well as disability prevention and management Table II and III.
I acknowledge the exemplary technical support of Janet Couturier and the library assistance of Carol Spencer.
REFERENCES 1. Report of the International Leprosy Association Technical Forum. The global situation of leprosy control of the 21st century. Int J Lepr Other Mycobact Dis 2002;70:521-2. 2. Visschedijk J, van de Broek J, Eggens H, Lever P, van Beers S, Klatser P. Mycobacterium leprae—millennium resistant! Leprosy control on the threshold of a new era. Trop Med Int Health 2000;5:388-99. 3. Pfeifer LA. A summary of Hansen’s disease in the United States—2001. Presented at the Seminar on Hansen’s Disease, National Hansen’s Disease Program; February 26, 2003. 4. Naafs B. Viewpoint: leprosy after the year 2000. Trop Med Int Health 2000;5:400-3. 5. Bryceson A, Pfaltzgraff RE. Diagnosis. In: Bryceson A, Pfaltzgraff RE. Leprosy. Edinburgh: Churchill Livingstone; 1990: p. 57-75. 6. Report of the International Leprosy Association Technical Forum. Diagnosis and classification of leprosy. Int J Lepr Other Mycobact Dis 2002;70:523-31. 7. WHO Expert Committee on Leprosy. 7th Report (WHO Technical Report Series, No.874). Geneva: World Health Organization, 1998. 8. Weng XM, Chen SY, Ran SP, Zhang CH, Li HY. Immunohistopathology in the diagnosis of early leprosy. Int J Lepr Other Mycobact Dis 2000;68:426-33. 9. Buhrer-Sekula S, Sarno EN, Oskam L, Koop S, Wichers I, Nery JA, et al. Use of ML dipstick as a tool to classify leprosy patients. Int J Lepr Other Mycobact Dis 2000;68:456-63. 10. Scollard DM, Gillis TP, Williams DL. Polymerase chain reaction assay for the detection and identification of Mycobacterium leprae in patients in the United States. Am J Clin Pathol 1998; 109:642-6. 11. Dharmendra. Classification of leprosy. In: Hastings RC. Leprosy. Edinburgh: Churchill Livingstone; 1985. p. 88-99. 12. Ridley DS, Jopling WH. Classification of leprosy according to immunity. A five-group system. Int J Lepr Other Mycobact Dis 1966;34:255-73. 13. World Health Organization. Leprosy Elimination Advisory Group. Guide to eliminate leprosy as a public health problem: multidrug therapy cures leprosy, stops transmission and prevents disabilities. Geneva: Leprosy Elimination Group, World Health Organization; 2000. 14. Rose P, Waters MF. Reversal reactions in leprosy and their management. Lepr Rev 1991;62:113-21.
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15. Guerra JG, Penna GO, de Castro LC, Martelli CM, Stefani MM. Erythema nodosum leprosum: clinical and therapeutic update. An Bras Dermatol 2002;77:389-407. 16. Becx-Bleumink M, Berhe D. Occurrence of reactions, their diagnosis and management in leprosy patients treated with multidrug therapy; experience in the leprosy control program of the All Africa Leprosy and Rehabilitation Training Center (ALERT) in Ethiopia. Int J Lepr Other Mycobact Dis 1992;60:173-84. 17. Moschella SL. The lepra reaction with necrotizing skin lesions. A report of six cases. Arch Dermatol 1967;95:565-75. 18. Ortiz Y, Finer M. Lucio’s leprosy (diffuse lepromatous leprosy). II. Recent advances, clinical and laboratory data. Dermatol Rev Mex 1978;22:141-63. 19. Rea TH. Lucio’s phenomenon: an overview. Lepr Rev 1979;50: 107-12. 20. Duncan ME, Melsom R, Pearson JM, Ridley DS. The association of pregnancy and leprosy. I. New cases, relapse of cured patients and deterioration in patients on treatment during pregnancy and lactation—results of a prospective study of 154 pregnancies in 147 Ethiopian women. Lepr Rev 1981;52:245-62. 21. Lockwood DN, Sinha HH. Pregnancy and leprosy: a comprehensive literature review. Int J Lepr Other Mycobact Dis 1999; 67:6-12. 22. Gebre S, Saunderson P, Messele T, Byass P. The effect of HIV status on the clinical picture of leprosy: a prospective study in Ethiopia. Lepr Rev 2000;71:338-43. 23. Lucas S. Human immunodeficiency virus and leprosy. Lepr Rev 1993;64:97-103. 24. WHO Study Group on Chemotherapy of Leprosy for Control Programmes. Chemotherapy of leprosy for control programmes: report of a WHO study group. Geneva: World Health Organization; 1982.
25. Ji B. Prospects for chemotherapy of leprosy. Indian J Lepr 2000;72:187-98. 26. Bhattacharya SN, Sehgal VN. Reappraisal of the drifting scenario of leprosy multi-drug therapy: new approach proposed for the new millennium. Int J Dermatol 2002;41:321-6. 27. van Brakel WH, Khawas IB. Silent neuropathy in leprosy: an epidemiological description. Lepr Rev 1994;65:350-60. 28. Talwar GP. An immunotherapeutic vaccine for multibacillary leprosy. Int Rev Immunol 1999;18:229-49. 29. Azulay DR. Antileprosy vaccinations. An Bras Dermatol 2002; 77:489-94. 30. Zaheer SA, Misra RS, Sharma AK, Beena KR, Kar HK, Mukherjee A, et al. Immunotherapy with Mycobacterium w vaccine decreases the incidence and severity of type 2 (ENL) reactions. Lepr Rev 1993;64:7-14. 31. Lockwood DN. The management of erythema nodosum leprosum: current and future options. Lepr Rev 1996;67:253-9. 32. Stanley JN, Kirnan KU, Pearson JM. The use of colchicine in the management of type II reaction (erythema nodosum leprosum). Lepr Rev 1984;55:317-8. 33. Nery JA, Perisse AR, Sales AM, Vieira LM, Souza RV, Sampaio EP, et al. The use of pentoxifylline in the treatment of type 2 reactional episodes in leprosy. Indian J Lepr 2000;72:457-67. 34. Miller RA, Shen JY, Rea TH, Harnisch JP. Treatment of chronic erythema nodosum leprosum with cyclosporine A produces clinical and immunohistologic remission. Int J Lepr Other Mycobact Dis 1987;55:441-9. 35. Escalona E. La lepra en la actualidad. Medico 1954;4:26-8. 36. Leprosy disabilities: magnitude of the problem. Wkly Epidemiol Rec 1995;70:269-75. 37. Ladhani S. Leprosy disabilities: the impact of multidrug therapy (MDT). Int J Dermatol 1997;36:561-72.
REVIEW
An update on the diagnosis and treatment of leprosy
Samuel L. Moschella, MD Burlington, Massachussetts
A
lthough the World Health Organization (WHO) has assumed the authoritative role for the guidelines for the diagnosis and treatment of leprosy, certain endemic countries such as India and Brazil and countries with traditional interest in the disease such as England and the United States have utilized their own programs which have been modified by the WHO. The prevalence of leprosy in endemic areas has been significantly reduced, but unfortunately the incidence continues to be the same. However, the WHO is optimistic about the elimination of leprosy as a public health problem in the near future; such optimism is not shared by many leprologists. The practicing physician especially in the non-endemic areas, such as the USA, should be aware of the current diagnostic and therapeutic approach to leprosy as recommended not only by the National Leprosy Center of the USA and its satellite clinics, but also by the WHO. If the practicing dermatologist wants to treat leprosy and become a ‘‘dermatoleprologist,’’ it is mandatory that he is knowledgeable about its diagnosis, treatment, reactions, the associated neuritis, and the prevention and management of its disabilities. With the potential decline of leprosy, leprosy control will become part of primary health care, which must promote early detection, adequate treatment, prevention, and management of disabilities.
GLOBAL SITUATION1,2
Over the years through expert committees and study groups, the WHO has assumed responsibility for recommending guidelines especially to underdeveloped countries for the management of leprosy. These guidelines take into consideration not only
From the Department of Dermatology, Lahey Clinic Medical Center. Funding sources: None. Conflicts of interest: None identified. Reprint requests: Samuel L. Moschella, MD, Dermatology Department, Lahey Clinic Medical Center, 41 Mall Road Burlington, MA 01805. E-mail: [email protected]. J Am Acad Dermatol 2004;51:417-26. 0190-9622/$30.00 ª 2004 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2003.11.072
their efficacy, but also the cost and availability of the necessary personnel. Although it has become literally the authoritative resource, one must recognize that in some endemic areas such as Ethiopia, Brazil, and India, and in the non-endemic areas such as the United States and England, there are research and study centers assessing, developing, and recommending modifications of the current diagnostic and therapeutic approaches. Leprosy is regarded as a special public health problem because of its capacity to cause permanent disabilities with their social consequences of discrimination and stigma. The three main objectives in controlling leprosy are to interrupt transmission, cure patients, and prevent development of deformities. In 1981, the number of leprosy patients in the world was more than 12 million. With the implementation of multiple drug therapy (MDT) in 1982 and the World Health Assembly resolution in 1991, the global effort for the ‘‘Elimination of Leprosy as a Public Health Problem’’ was prioritized and has resulted in over 10 million patients being cured. In countries with more than 100 cases registered, the WHO reported in January 2002 that, in the year 2000, a total of 597,232 cases were registered and 719,330 new cases were diagnosed.1 This report emphasized the reduction of the global prevalence from 12 per 10,000 in 1985 to slightly below 1 per 10,000 in 2002. Of the 122 countries in which leprosy was considered endemic, 107 have achieved the ‘‘elimination target’’ (1 per 10,000). Approximately 83% of the leprosy cases live in six countries: Nepal, Madagascar, Myanmar, Indonesia, and especially India and Brazil. As of 2001, there are 6,518 ‘‘active’’ cases of leprosy registered in the USA.3 The number of new cases remained about the same until the last 10 years during which there has been a significant increase. This increase may be a result of increased case detection campaigns and expansion of geographical coverage by leprosy services in endemic countries. Encouraged by the success of the multiple drug therapy, the WHO assembly adopted, in 1991, a declaration to eliminate leprosy as a public health problem by the year 2000. Since it was apparent that the goal was not to be achieved, a global alliance for 417
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the elimination consisting of a core group of the governments of leprosy endemic countries, the Nippon Foundation, the International Federation of Antileprosy Association, Novartis, and the WHO was formed. It will cooperate with other institutions to eliminate leprosy by the end of 2005. The past pessimism by various authors, which I share, still persists.4 This lack of enthusiasm is fueled by the following: 1. There is no sound evidence that the leprosy elimination strategy has had an impact on transmission so far. 2. The incidence has increased in spite of the significant reduction of the prevalence. 3. Leprosy is not only a bacterial, but also an immunologic disease. Failure of early diagnosis and treatment will increase neural disease. After patients are cured by MDT, a quarter of them experience immunologic nerve damage reactions. Emphasis on elimination can eclipse the quality of care necessary to prevent the disability, which will prevail long after 2005. 4. Other areas that need to be addressed which could have a significant impact on elimination are the recognition of the hidden prevalence, the subclinical infected, the possible role of the non-human reservoir or of sources of infection in the environment responsible for transmission, the need for a skin or serologic tests to diagnose subclinical, early, or questionable cases, the availability of an effective, cheap, proven prophylactic and possible immunotherapeutic vaccine, and the need of personnel capable of making an early diagnosis and to clinically differentiate paucibacillary (PB) and multibacillary (MB) disease.
At the Seventh Meeting of the WHO Expert Committee on Leprosy in 1997, a case of leprosy was defined as an individual who has not completed a course of treatment and has one or more of the three cardinal signs:7 Hypopigmented or reddish skin lesions with loss of sensation Involvement of the peripheral nerves as demonstrated by their thickening and associated loss of sensation Skin-smear positive for acid-fast bacilli The specificity of the diagnosis based on the presence of anesthetic hypopigmented or erythematous macular lesions is reduced in multibacillary cases because the lesions can be less distinct and less anesthetic. Consequently macular anesthetic lesions as a single diagnostic criterion for multibacillary (MB) disease has resulted in up to 30% of patients to be missed; this contrasts with patients with distinct maculoanesthetic lesions of paucibacillary (PB) disease, which are reportedly diagnostic in 90% of cases. In Ethiopia where all 3 cardinal signs were used, the diagnostic sensitivity was 97%.1 Peripheral nerve enlargement usually appears later than skin lesions. The most commonly involved nerves are the ulnar and common peroneal. The presence of one or more enlarged nerves is seen more commonly in multibacillary disease. False positive reporting of nerve involvement may result from poor examination technique or the nonspecific enlargement of nerves such as in manual workers. To improve the certainty of the diagnosis of leprosy, a balanced approach to the diagnosis is strongly recommended and would be the appreciation of the presence of a thickened nerve and one other diagnostic sign such as: typical hypopigmented or erythematous skin lesions with or without sensory loss or typical nerve-function impairment such as loss of sensation of palms or soles Leprosy can present as a purely neural disease without skin lesions; the so-called neuritic leprosy. Nerve biopsy is confirmatory. The incidence is 0.5% in Ethiopia, 4.6% in India and 8.7% in Nepal. The diagnostic specificity of skin smears is almost 100%; however, its sensitivity is rarely more than 50% because smear positive patients represent only 1050% of cases. The inherent problems of skin smears are the logistics and the reliability of the technique of taking, staining, and interpretting the slide. Skin smears identify those with multibacillary disease who are the most infectious and also those patients who are experiencing clinical relapses.
DIAGNOSIS OF LEPROSY5,6
Leprosy is a slowly progressive infectious disease caused by Mycobacterial leprae and complicated by potential intermittent hypersensitivity reactions (the so-called lepra reactions). It is highly infective with low pathogenicity and virulence and has a long incubation period. The skin, superficial peripheral nerves, anterior chamber of the eyes, and testes, all cooler parts of the body are the most frequently affected organs. Its geographic distribution varied in the past, but presently it is endemic mainly in subtropical areas. Early accurate diagnosis and therapy are most important for the control of the disease, the management of the patient, and prevention of disabilities. Underdiagnosis promotes transmission and results in unnecessary suffering and deformities; overdiagnosis is responsible for unnecessary treatment, stress, stigma, and misleading epidemiologic statistics.
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Tissue biopsies are used to make a histologic diagnosis, to classify the disease, to provide material for inoculation of footpad of mice, and for research purposes. The biopsy cannot be regarded as the diagnostic gold standard since a number of them can be nondiagnostic or doubtful. In practice, a clinical and histopathologic correlation may be necessary for diagnosis. Although the histopathologic diagnostic specificity of non-reactive disease is high, the histopathologic differentiation of relapse from reversal can be difficult or impossible. In a study in China, immunohistopathologic studies staining biopsies of PB patients with phenolic glycolipid-1 antigen proved to be more specific diagnostically than routine hematoxylin and eosin histopathologic examination.8 In the field, the diagnosis and classification of leprosy have been based on clinical examination and skin smears when facilities are available. Diagnostic tests such as histologic examination of involved tissues, inoculation of footpads of mice, serologic and skin testing, and polymerase chain reaction studies have been confined to countries which have such studies available to their practicing physicians and in academic and research centers. Two laboratory tests, which so far have not played a significant role in the diagnosis of leprosy, are the serological tests for anti-PGL-1 antibodies and the PCR test. There are two methods to determine the presence of anti-PGL-1 antibodies, the M. leprae particle agglutination assay (MLPA) and the enzymelinked immunosorbent assay which was further refined into a ‘‘dipstick’’ assay which has greater specificity.9 The PGL-1 antibody testing is specific and sensitive in patients with MB disease, but unfortunately it is not very helpful in the diagnosis of PB disease and is unable to predict, among contacts of known cases in the general population, who will develop the disease. PCR testing is a highly sensitive and specific diagnostic tool. Unfortunately, in countries where it is available, such as at the National Hansen Disease Center, Baton Rouge, Louisiana, USA, it has not proved so far to be as effective diagnostically as anticipated in indeterminate or paucibacillary disease.10
CLASSIFICATION OF LEPROSY11
In 1966, Ridley and Jopling created a classification of leprosy, based on the immunologic response of the host to M leprae, into a five-group system: TT (polar tuberculoid), BT (borderline tuberculoid), BB (borderline), BL (borderline lepromatous), and LL (polar lepromatous) (Table III).12 In 1982, the WHO study group for chemotherapy for control programs recommended the classification of all patients be based on Ridley-Joplin classification and the esti-
mated bacterial load in skin-slit smears. The TT and BT patients who had a bacillary index (BI) # 2+ were classified as paucibacillary disease, and BB, BL, and LL patients who had a BI > 2+ were classified as multibacillary disease. The BI reflects the number of acid-fast bacilli per average oil immersion field and is expressed on a 0-to-6+ semilogarithmic scale; BI of 2+ is the presence of 1 to 10 bacilli per 10 oil immersion fields. In 1988, the WHO Expert Committee on Leprosy, to avoid further treatment failure of PB patients with positive skin-slit smears, recommended such cases be classified as multibacillary disease and consequently any patient with a positive skin smear is classified as multibacillary disease. In the USA, the Public Health Service recommends that the classification of leprosy should be made on clinical evaluation, and skin smears from several sites and skin biopsies which can be read if necessary by the National Hansen’s Disease Center, Baton Rouge, Louisiana. The Ridley-Jopling classification is used. In general, PB disease is equivalent to indeterminate I, TT (tuberculoid), and BT (borderline tuberculoid) disease, and MB is equivalent to BB (borderline), BL (borderline lepromatous) and LL (lepromatous) disease with the Ridley-Jopling classification. In the US, the terms paucibacillary and multibacillary are used to direct drug therapy. In 1998, the WHO Expert Committee on Leprosy declared skin-slit smears were not essential for multiple drug therapy (MDT) and the number of clinical lesions present was to be the basis for classification.13 This was motivated by the unavailability or unreliability of the skin smear in many programs and the potential for transmitting HIV disease and hepatitis by unsterile techniques. The recommended clinical diagnostic guidelines are as follows: patients who are not experiencing reactions and have less than five skin lesions are to be classified as paucibacillary disease (PB), and those with greater than five skin lesions are to be classified as multibacillary (MB). Unfortunately, there will be a sufficient number of MB cases classified as above PB to cause some concern because of the potential for their inadequate treatment.
REACTIONS13,15
There are two main categories of reactions in leprosy: Type I14 reaction, which is called a reversal lepra reaction and is an example of Type IV cell mediated allergic hypersensitivity reaction (Coombs and Gell); and Type II lepra reaction,15 which is reported as erythema nodosum leprosum and is an example of Type III humoral hypersensitivity reaction (Coombs and Gell) (Table II). Among the
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precipitating factors are physical and mental stress, multiple drug therapy, vaccines, pregnancy, surgical procedures, injuries, intercurrent infections, and other antibacterial treatments. Inflammatory edema of hands, feet, and face is seen in both types and is a sign of severe reaction. Nerve tenderness and pain are often associated with both types. The most common and frequent nerves involved are the ulnar, the facial, median, common peroneal, and posterior tibial nerves. The related physical impairment may be acute and dramatic such as facial paralysis or foot drop. The reversal reaction (Type I)14 occurs in borderline tuberculoid (BT), borderline (BB), and especially borderline lepromatous (BT) and possibly in tuberculoid (TT) leprosy. The present skin lesions become more erythematous, edematous, raised, and rarely ulcerated. Patients with BL, BB, and occasionally BT disease exhibit not only changes in the existing skin lesions but may develop similar new lesions. Erythema nodosum leprosum (ENL) (Type II) reaction15 is immunologically characterized by immune complex deposition in tissue space, blood, and lymphatic vessels, which give rise to acute inflammatory foci. It usually occurs most frequently in patients with LL and occasionally in those with BL. Increased cell-mediated immunity may play a role in the precipitation of an attack. The tumor necrosis factor alpha is elevated in ENL. During therapy or occasionally during pregnancy, patients with BB to LL disease can develop ENL characterized by the sudden appearance of crops of erythematous tender nodules or plaques, and rarely vesicular, pustular, or necrotic lesions. The eruption favors the extensor surfaces of the extremities and face. Other signs and symptoms are fever and malaise, iritis, epistaxis, muscle and bone pain, nerve pain, joint pain, lymphadenitis, epididymo-orchitis, and proteinuria. A third rare type of reaction, the Lucio phenomenon,15,16 is usually restricted to Central and South America and immigrants from those areas. It occurs in a subtype of lepromatous leprosy called the primary diffuse lepromatous leprosy (la lepra bonita) characterized by a diffuse infiltration of the skin by a granulomatous process heavily loaded with mycobacterium leprae. Significant nasal mucosa involvement usually occurs with subsequent nasal destruction. Ocular and peripheral nerve involvement are significantly less frequent than in the other subtypes of lepromatous leprosy. Intermittent fever, generalized lymphadenopathy, and splenomegaly may be seen. The eruption (the Lucio phenomenon) is characterized by the presence of symmetrical erythematous, black, stellate, necrotic lesions of the
extremities and occasionally the face. The patients are usually on no treatment when it occurs.
HANSEN’S DISEASE AND PREGNANCY20,21
It is not uncommon for leprosy to present itself during pregnancy or early puerperium. Because of alterations in immune responses during pregnancy, leprosy patients who become pregnant are more prone to develop type I and II reactions, a downgrading of their disease, and relapses. Type II reaction usually occurs during pregnancy, especially during the third trimester and lactation. Type I reaction occurs, especially during puerperium. Infants run a relatively high risk of contracting leprosy from untreated mothers, especially if she has BB or LL disease. It has been recommended that rifampin be given only as a single monthly dose during pregnancy, but dapsone and clofazimine can be used or continued. For reactions, prednisone and clofazimine can be given, but thalidomide should be avoided. It is advisable to postpone pregnancy temporarily during post-therapy period if there is evidence of reaction, relapse, or neuritis.
HANSEN’S DISEASE AND HIV DISEASE22,23
Unlike in tuberculosis, HIV disease has not had a significant impact on the clinical course of treated and untreated leprosy. However, it has been reported that the neuritis in co-infected people can be more severe and the reversal reaction may be more frequent after therapy. In endemic areas of HIV disease and leprosy, there does not appear to be a greater incidence of leprosy among HIV patients. It may be because of the very slow proliferation of the bacilli or the prolonged incubation period, or perhaps a particular cellular mechanism involved in its pathogenesis.
THERAPY OF NONREACTIVE DISEASE24-26
In 1981, the WHO Study Group recommended multiple drug therapy (MDT) for the following reasons:24 1. To address dapsone resistance and to discourage resistance to other drugs to be used. 2. To promote compliance and to get away from long-term monotherapy such as dapsone. 3. To keep rifampin in all therapeutic regimens because of its powerful bactericidal action and its effectiveness even when taken once a month. 4. To promote compliance and cost effectiveness. In 1997, the WHO Expert Committee suggested that it might be possible to reduce duration of MDT for multibacillary disease from 2 years to one year and also recommended the treatment of a single PB
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lesion with one dose of ROM (rifampin, ofloxacin, and minocycline).26 The current WHO recommended MDT for adults is as follows: 1. For paucibacillary disease (PB), 600 mg rifampin monthly and 100 mg dapsone daily with six cycles in 9 months. 2. For multibacillary disease (MB), 600 mg rifampin and 300 mg clofazimine monthly and 100 mg dapsone and 50 mg clofazimine daily with 24 cycles in 36 months or 12 cycles in 18 months 3. For single PB lesion, rifampin 600 mg, ofloxacin 400 mg, minocycline 100 mg. Because of a lack of long-term follow-up, this recommendation should be considered experimental. Single-lesion leprosy, which is often indeterminate leprosy, heals spontaneously in 80% of patients. It is too early to determine if those of the 20% who develop classifiable leprosy will benefit from single ROM treatment. It may cure some patients but will only delay the onset of multibacillary disease in others. In the United States, a biopsy of a suspicious lesion is recommended to establish the diagnosis and deliver the appropriate treatment. Other drugs with anti-mycobacterial properties, which may be used if needed as substitutes in the above current therapeutic programs are rifabutin, ofloxacin, sparfloxacin, levofloxacin, minocycline, and clarithromycin. Although the diagnostic and therapeutic guidelines advocated by the WHO have significantly impacted on global prevalence rate, practitioners especially in the USA should be aware that the Public Health service recommends the classifications of the disease into paucibacillary and multibacillary disease for its recommendations for treatment. In the United States, MDT has been standard therapy since the 1970s. During this period, 3 years of daily dapsone, rifampin, and clofazimine was recommended, and if there was suspicion of dapsone resistance, severe and widespread neuropathy, or ocular disease, dapsone was recommended to be given indefinitely. In 1990, a relatively short-term therapy was introduced in the United States under the FDA-approved protocols which has proven very effective and without significant toxicity. The current recommended standard treatment regimens for Hansen’s disease in the United States are outlined in Table I. The strengths of MDT are that it obviates and prevents dapsone resistance, quickly reduces infectivity, and results in fewer relapses and reactions, and consequently, fewer disabilities. The shortcomings of MDT are the long duration of therapy with
Table I. Public health service recommendation for treatment of leprosy
1. Paucibacillary (PB): Dapsone 100 mg daily plus Rifampin 600 mg daily for 1 year 2. Multibacillary (MB): Dapsone 100 mg daily plus Rifampin 600 mg daily plus clofazimine 50 mg daily for 2 years 3. The follow-up: For treated PB disease every 6 months for 5 years and for MB disease every 6 months for 10 years
consequential reduction of compliance, encouragement of default, and creation of operational difficulties. Since WHO/MDT appears to have been effective, safe, and well tolerated and the risk of relapse is low, unlike the USA, the WHO does not advocate posttherapy surveillance. Patients are advised to report as soon as they note any skin, eye, or nerve changes. Fortunately, post-therapy relapse, reaction, and silent neuropathy occur infrequently. Until sufficient data of post-therapy complications exists, treated paucibacillary disease should be followed for at least three to five years, and treated multibacillary disease should be followed for at least five to ten years. Silent neuropathy is described as a progressive sensory or motor impairment which occurs in the absence of cutaneous type I or II reactions and is characterized by a lack of involved nerve tenderness and burning or shooting pain, paresthesias, or numbness.27
VACCINATION
Anti-leprosy vaccination can be immunoprophylactic or immunotherapeutic.28-30 The immunoprophylactic aim is to restore the host recognition of shared mycobacterial antigens to promote TH1 responses to them, to induce CD8 cytotoxic cells, and to downregulate the proportion of T cells producing interleukins 4 and 5. The aim of immunotherapy is to switch off the mechanisms leading to immunopathology and to increase intracellular mechanisms by which bacilli are killed. The first vaccine used was BCG, but its failure to protect certain populations clearly indicated that an improved vaccine against leprosy was needed. Among the vaccines being used or explored are Mycobacterium W. (Talwar, 1978), Mycobacterium ICRC (M avium intracellulare) (Deo et al, 1981), bacillus Calmette´ rin plus heat-killed M leprae (Convit, 1992), Gue Mycobacterium tufu (Iushm and Kalianina, 1995), and Mycobacterium habana (Singh et al, 1997).29 The enthusiasm for use of vaccines has lessened because of the significantly favorable impact of MDT on leprosy. However, one cannot deny the potential usefulness of a proven effective vaccine in highly endemic countries such as India and Brazil. Some of
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Table II. Characteristic features of reactional leprosy
Type I reaction (Reversal) Type II reaction (erythema nodosum leprosum-ENL) Lucio phenomenon
Complication of types of - Rare in Tuberculoid leprosy - Borderline (BB, BT, BL) Clinical features -
-
-
-
-Lepromatous leprosy (LL) and occasionally Borderline lepromatous (BL) Occurs during 6 to 18 - Can occur before months of treatment treatment but tends to occur later in treatment Constitutional signs and - In severe cases constitutional signs symptoms in severe and symptoms cases - Erythematous tender nodules Lesions become appear in crops especially erythematous and extremities and face edematous; in severe cases ulcerate (Lazarine - Vesicular, pustular, suppurative lesions can occur leprosy) - Edema of face, hands, and feet Edema of affected extremities and face may - Orchitis, lymphadenitis, dactylitis, epistaxis, and proteinuria occur
- Diffuse lepromatous leprosy; endemic Mexico and Costa Rica - No constitutional signs or symptoms
Neuropathic and ocular changes
Course
Treatment
- Few days but can be prolonged, frequent, and recurrent - Prednisone, non-steroidal - NSAID, thalidomide, anti-inflammatory drugs increase dose (NSAID) of clofazimine, systemic corticosteroids
- Pain and swelling of one or more nerves; nerve abscesses can form - Sudden appearance of claw hand, foot drop, facial palsy with or without Lagophthalmus and complicating exposure keratitis - Usually persists for few months
- Widespread painful swelling of peripheral nerves - Iridocyclitis and scleritis of eyes
- Pseudomyxedematous facies - Madarosis with or without generalized and diffuse hair loss - Extensive areas of anhidrosis - Early and severe destructive rhinitis - Erythema necrotisans-flame or geographic shaped necrotic lesions anteceded sometimes by hemorrhagic blisters; appear in crops, favor extremities and sometimes the face; heal with superficial scarring - No orchitis - Labs—anemia, elevated sedimentation rate, positive STS - Acral distal symmetrical anesthesia usually with no significant aggravation - Muscle atrophy and paralysis late - Minimal ocular involvement with no iritis - Depends on the severity of the reaction and response to MDT - Systemic corticosteroids - Thalidomide is ineffective
the best information about vaccination is from India where the Mycobacterium W and ICR vaccines are currently being used. In the field, with the use of vaccine ‘‘W’’ as an adjunct to chemotherapy, the following observations were noted:28 1. The vaccine expedited bacterial clearance and accelerated clinical regression of the lesions. 2. It shortened significantly the period of release of the patients from treatment.
3. It was effective in inducing a fall in the bacterial index in multibacillary patients who are poor or nonresponders to the standard multidrug therapy. 4. It promoted the conversion of the lepromin from negativity to positivity. 5. There was a histopathologic upgrading. 6. The vaccine was tolerated and the incidence and severity of the type II reaction was reduced. 7. No increased incidence of neuritis was seen.
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Table III. Ridley-Jopling classification
Characteristics Indeterminate Tuberculoid (TT-Polar) Borderline tuberculoid (BT) Borderline (BB) Borderline lepromatous (BL) Lepromatous (LL + Polar)
Cutaneous
One or few One or few lesions; lesions; hypopigmented sharply or erythematous marginated; scaling macules; favors macules or extremities, buttock, or face plaques; sometimes elevated edges
Neuropathic Lesions slightly changes hypesthetic, no peripheral nerve enlargement
Lesions anesthetic sometimes enlarged nerve in area of lesion
Nil Nil Bacterial (paucibacillary) (paucibacilindex lary) (Ridley’s logarithmic indices) Lepromin Variable Strongly test positive Reactions Nil Rare
Multiple and symmetrical erythematous and copper colored macules, later induration followed by nodulation of face especially ears and nose, extremities especially joints, and trunk; madarosis of eyebrows; nasal mucosal ulceration Usually no Lesions Moderate Lesions sensory slightly anesthetic anesthetic impairment in anesthetic lesions asymmetrical early stages; widespread widespread several later and less and peripheral symmetrical asymmetrical asymmetrical nerves peripheral peripheral peripheral involved neuropathy nerve nerve of arms and involvement involvement legs with stocking and glove anesthesia and of the facial nerve; Eye involvement (conjunctiva, cornea, and iris) 2+-3+ 4+-5+ 6+ and greater Nil or scarce (multibacillary) (multibacillary) (multibacill(paucibacillary) ary) or multibacillary Several succulent Many, Few to many roughly plaques erythematosymmetrical with sharply hypochromic shiny demarcated plaques with erythematous central area scaling and and edges surface and sometimes sloping into well-defined hyposurrounding margins pigmented normal skin; which macules, large may have papules, erythematous small satellite nodules irregular lesions and with infiltrated is usually sloping bands with annular edges central uninvolved anesthetic areas Weakly positive Reversal (Type I) Negative Reversal (Type I) Negative Reversal (Type I) and/or ENL (Type II) Negative ENL (Type II)
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TREATMENT REACTIONS
Unfortunately in spite of the significant advances in the chemotherapy of the disease in the last ten years, the understanding of the etiology and management of reactions has not changed much. MDT has not significantly impacted on the incidence of the reversal reaction (Type I). The treatment of the reaction14,16,31 depends on its severity, the type of the reaction, the presence of neuritis, facial involvement in Type I reaction, pregnancy, and drug allergies or adverse drug reactions. If Type I reaction14 is severe or associated with neuritis or facial lesions are involved, systemic corticosteroids are indicated. In milder cases without neuritis, the nonsteroid antiinflammatory drugs may be helpful. With the use of clofazimine in the WHO multidrug therapy, the frequency of ENL Type II reaction has been significantly reduced to as low as 5%. In Type II reaction15,16,31 without significant neuritis, thalidomide is effective, but in the presence of neuritis or iritis, systemic corticosteroids are necessary. Topical steroids and atropine are used for reactive iritis. Clofazimine in higher doses can sometimes permit the use of lower doses of corticosteroids. Colchicine32 and pentoxifylline33 have been reported to be effective and may be useful as adjunctive drugs in the treatment of Type II reactions. In refractory cases immunomodulatory agents such as cyclosporin A,34 and intravenous IgG might be considered. Lucio phenomenon17,18,19 is usually controlled by systemic corticosteroids. In the late 1940s and early 1950s, Mexican leprologists reported the control of Lucio phenomenon in untreated patients with the initiation of dapsone therapy;35 unfortunately in my limited experience, monotherapy with dapsone in the past and MDT presently did not make a significant therapeutic impact on the Lucio phenomenon. Thalidomide is ineffective. In severe, non-responding cases, immunomodulatory and cytotoxic drugs, such as Imuran or cyclophosphamide with systemic corticosteroids with or without plasmapheresis have been used.
involved followed by the feet and eyes. There is an estimated 3 million people with physical impairments with resultant disabilities. Approximately 4% of newly diagnosed patients present with grade II disabilities, which are visible deformities or damages. However, grade I disability, that is the presence of anesthesia without damage is important because these patients are at serious risk of developing serious impairments and deformities. The reported incidences of grade II disabilities are 3% in patients in Southeast Asia, 11% of patients in Africa, and 5% of patients in America. Any leprosy program must incorporate the prevention of disabilities and rehabilitation. Among the important efforts for prevention are an initial and periodic measurement of neural impairment, aggressive treatment of reactions, provisions for the therapy and prevention of injuries to the hand, of foot ulcers, of eye disease, and their complications, and instructions in self-care. The best methods for early detection of nerve impairment are palpation for nerve enlargement and use of sensory testing. Early detection and treatment of reactions significantly reduce and prevent nerve damage with its resultant impairment. The initiation of systemic steroid therapy depends on the magnitude and duration of nerve function impairment and/ or nerve tenderness. It has been reported that 7% of new patients have at first examination silent neuropathy; 75% of all silent neuropathy was diagnosed during the first year of treatment.27 Patients with extensive skin involvement, more than three enlarged nerves or a positive skin smear, are at a greater risk to develop silent neuropathy. The leprous neuropathy responds to a prednisone taper over about a four to six month period. Patients treated for early nerve impairment regain 60% of their nerve function. Neural impairment up to six months duration may be benefited by systemic corticosteroid therapy. The role of surgery in the management of nerve involvement is controversial. There is no data to suggest that steroids given prophylactically prevent impairment.
PREVENTION OF DISABILITIES AND REHABILITATION36,37
The socioeconomic impact resulting from the physical and psychological disabilities of leprosy continues to be a burden in endemic countries. 25% of leprosy patients have some degree of disability, which are greatest in patients with BL and LL disease. It is greater in the older age group and males. Duration of disease and disability are directly proportional to each other. Hands are most frequently
CONCLUSIONS
In spite of its relative simplicity, the classification of leprosy into paucibacillary and multibacillary disease based on lesion count in conjunction with an MDT program has proven to be effective in the reduction of the prevalence without significant relapse or Type I and II reactions. In fact, the incidence and severity of these reactions, especially Type II, have been reduced. When facilities are available to do the necessary laboratory studies, it is advisable to
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continue to use the Jopling-Ridley classification for scientific communications, teaching, and patient care. Because the incidence appears to have remained stable in spite of MDT, the projection of the WHO program for the eradication of leprosy by 2005 appears to be unrealistic. In the absence of a proven cost effective vaccine and because of the time constraints for vaccine trials, there is presently no alternative to MDT in trying to break the chain of transmission of M. leprae, however. I share the pessimism of some leprologists. The question being asked is: will the repeated postponements of the goal elimination dates undermine the confidence and support of the involved governments, institutions, and public for this strategy? I would like to echo support for the stance of Vissehedigk et al2 which is: sustainable leprosy control which consists of early detection of patients, adequate treatment, and providing comprehensive care for the prevention of disabilities and rehabilitation, and continuous research to close the substantial gaps in the knowledge of leprosy transmission and epidemiology should be our goal for the foreseeable future rather than elimination. Unlike tuberculosis, HIV disease has not yet demonstrated a significant impact on leprosy and vice versa. Pregnancy can precipitate relapse, as well as Type I and Type II reactions. Unfortunately, there are no skin tests or serologic studies that facilitate the recognition of ‘‘carriers,’’ or the diagnosis of paucibacillary disease. The pathogenesis and treatment of the Lucio’s phenomenon need to be established. In endemic regions, leprosy continues to be a public health problem. Defining leprosy control purely by prevalence side-steps the real issues such as: 1. Control programs need tests such as a skin or serologic test for recognition of ‘‘carriers’’ in order to help reduce the incidence. 2. Research is needed to shorten treatment schedules and to reduce defaulter rates and costs. 3. Treatment of the infection, reactions, and neuritis is still far from ideal. 4. The use of an effective vaccine may play a major role in the prophylaxis and therapy of leprosy in high-risk regions. 5. Research into the true incidence of leprosy in endemic areas is essential. 6. Control programs need a more detailed understanding of M. leprae to permit more logical interventions. 7. It is essential to minimize irreversible physical damage, which leads to disability and stigmatization.
Although, the prevalence rate should continue to decline, the major problems such as the disabilities among the old ‘‘cured’’ patients and those of the newly diagnosed patients must continue to be addressed. Because of the lack of the knowledge necessary to reduce the incidence of leprosy, we have to continue to invest heavily in the effort to reduce the prevalence and hopefully the incidence secondarily. It is also important to plan for the future by making leprosy control part of primary health care, which should promote early detection and adequate treatment as well as disability prevention and management Table II and III.
I acknowledge the exemplary technical support of Janet Couturier and the library assistance of Carol Spencer.
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